TY  - JOUR
AB  - Non-small cell lung cancer (NSCLC) has a poor prognosis with a 5 year survival rate of only ~ 10%. Important driver mutations underlying NSCLC affect the epidermal growth factor receptor (EGFR) causing the constitutive activation of its tyrosine kinase domain. There are efficient EGFR tyrosine kinase inhibitors (TKIs), but patients develop inevitably a resistance against these drugs. On the other hand, KCa3.1 channels contribute to NSCLC progression so that elevated KCa3.1 expression is a strong predictor of poor NSCLC patient prognosis. The present study tests whether blocking KCa3.1 channels increases the sensitivity of NSCLC cells towards the EGFR TKI erlotinib and overcomes drug resistance. mRNA expression of KCa3.1 channels in erlotinib-sensitive and -resistant NSCLC cells was analysed in datasets from Gene expression omnibus (GEO) and ArrayExpress. We assessed proliferation and migration of NSCLC cells. These (live cell-imaging) experiments were complemented by patch clamp experiments and Western blot analyses. We identified three out of four datasets comparing erlotinib-sensitive and -resistant NSCLC cells which revealed an altered expression of KCa3.1 mRNA in erlotinib-resistant NSCLC cells. Therefore, we evaluated the combined effect of erlotinib and the KCa3.1 channel inhibition with sencapoc. Erlotinib elicits a dose-dependent inhibition of migration and proliferation of NSCLC cells. The simultaneous application of the KCa3.1 channel blocker senicapoc increases the sensitivity towards a low dose of erlotinib (300 nmol/L) which by itself has no effect on migration and proliferation. Partial erlotinib resistance can be overcome by KCa3.1 channel blockade. The sensitivity towards erlotinib as well as the potentiating effect of KCa3.1 blockade is further increased by mimicking hypoxia. Our results suggest that KCa3.1 channel blockade may constitute a therapeutic concept for treating NSCLC and overcome EGFR TKI resistance. We propose that this is due to complementary mechanisms of action of both blockers.
AU  - Glaser, Felix
AU  - Glaser, Felix Martin
AU  - Hundehege, Petra
AU  - Bulk, Etmar Michael
AU  - Todesca, Luca Matteo
AU  - Schimmelpfennig, Sandra
AU  - Nass, Elke
AU  - Budde, Thomas
AU  - Meuth, Sven
AU  - Meuth, Sven G.
AU  - Schwab, Albrecht
DA  - 2021-09-15
DO  - 10.17879/32049543500
KW  - Cancer
KW  - Cancer therapy
KW  - Lung cancer
KW  - Physiology
LA  - eng
N1  - Scientific Reports 11 (2021) 18330, 1-12
N1  - Finanziert über die DEAL-Vereinbarung mit Wiley 2019-2022.
PY  - 2021-09-15
TI  - KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)
UR  - https://nbn-resolving.org/urn:nbn:de:hbz:6-52039545103
Y2  - 2024-11-21T17:37:14
ER  -